I. What every physician needs to know.

Von Willebrand factor (VWF) is important for primary and secondary hemostasis. VWF is a multifunctional protein that serves as a link between a damaged vessel wall and platelets, and is also a carrier for Factor VIII (FVIII). In primary hemostasis it binds to the platelet glycoprotein 1b and links it to the injured endothelium and other platelets. In secondary hemostasis, it binds to factor FVIII and protects it from early clearance. Von Willebrand disease (VWD) is highly heterogeneous and has many subtypes. Subtypes 1 and 3 are quantitative deficiencies in VWF, while type 2 subtypes are qualitative deficiencies--that is, there may be no deficiency but it is not working right. In total, there are 6 different classifications of VWD (1, 2A, 2B, 2M, 2N, and 3) based on distinct genetic and clinical properties.

Von Willebrand disease (VWD), especially the most common type 1 disease, can be very difficult to diagnose. A thorough family and bleeding history is essential in conjunction with laboratory evaluation to establish the diagnosis in more severely affected patients, while it may not to be positive to diagnose many patients with milder/borderline cases definitively, so they may carry a diagnosis of possible or probable VWD.

A. History Part I: Pattern Recognition:

The most common, milder type 1 VWD, which may not be diagnosed until later in life, is characterized by mucocutaneous bleeding. Many women with VWD are not diagnosed until they are being worked up for menorrhagia after menarche. Bleeding tends to be mucosal in nature (epistaxis, gums/dental, gastrointestinal, menstrual) or soft-tissue bleeding (bruising).

Severe VWD, which may be diagnosed early in life, presents with bleeding problems that are not confined to mucocutaneous bleeding and that may include muscle bleeds or spontaneous hemarthroses.

The inheritance pattern for types 1 and 2 (A, B, and M) are autosomal dominant, and the pattern for type 3 and 2N tends to be autosomal recessive.

B. History Part 2: Prevalence:

VWD is the most common congenital bleeding disorder and it affects men and women equally. Type 1 accounts for 70 percent of VWD and has an estimated prevalence as high as 1 percent. Type 2 WVD disease is much rarer, with subtypes 2A and 2B more prevalent. Type 3 is exceedingly rare (0.5 to 5.3/1,000,000).

C. History Part 3: Competing diagnoses that can mimic Von Willebrand disease.

Hemophilia A and other platelet disorders can mimic VWD. The most difficult bleeding disorder to differentiate from VWD is platelet-type VWD (also called pseudo-VWD), a platelet defect that mimics type 2B VWD. To differentiate the two, Ristocetin-induced platelet aggregations (RIPA) should be done with the patient's platelets rather than control platelets.

Congenital VWD should also be differentiated from a rare form of acquired VWD that can be associated with myeloproliferative disorders.

D. Physical examination findings.

Mucocutaneous bleeding is the most common symptom of mild VWD. More severe forms, such as type 3 VWD, present like severe hemophilia and can exhibit spontaneous joint and muscle bleeding.

E. What diagnostic tests should be performed?

A thorough personal and family history of bleeding symptoms is essential and is followed by laboratory testing.

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Bleeding time or PFA-100 (platelet function analyser-100) are both highly variable screening tests that are not good predictors of bleeding. Their use in the screening of VWD is questionable.

VWF:Ag is an ELISA (enzyme linked immunosorbent assay) to measure anti-VWF antibody quantitatively in the plasma.

FVIII activity is decreased if VWF is deficient either quantitatively or qualitatively.

RIPA is a diagnostic test for type 2B VWD, in which low doses of ristocetin promote increased aggregation when the patient's plasma is added to platelet-rich plasma.

See Table I.

Table I.

VWD subtype

VWF: Ag

VWF: RCoF

FVIII

RIPA

Platelet count

VWF multimers

1

↓

↓

↓

↓/nl

normal

normal

2A

↓

↓↓

↓

↓

normal

Large and intermediate multimers are absent.

2B

↓

↓↓

↓

increased

decreased

Large and intermediate multimers are reduced or absent.

2M

↓

↓

↓/nl

↓

normal

normal

2N

normal

normal

↓

normal

normal

normal

3

↓↓↓

↓↓↓

↓↓↓

↓↓↓

normal

absent

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Radiographic studies are necessary only to locate a bleed (e.g., retroperitoneal, intra-cranial).

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

Bleeding time is a screening test and is not very specific or sensitive. It does not replace a thorough bleeding history.

III. Default Management.

The primary goal of treatment is immediate cessation of bleeding in acute situations, or prevention of bleeding in more severe, chronic, and recurrent bleeding. Bleeding cessation or prevention can be achieved with Desmopressin (DDAVP®), clotting factor concentrate, anti-fibrinolytics (aminocaproic acid or tranexamic acid), and estrogen therapy.

A. Immediate management.

Severe, acute bleeding likely needs immediate increase or replacement of VWF. Desmopressin is generally used in mild cases and in particular has shown good response in patients with type 1 VWD. Desmopressin induces secretion of endogenous stores of FVIII and WVF into the circulation, and can increase plasma levels of Factor VIII and VWF to 3 to 5 times above the basal levels within 30 minutes of administration. Side effects of DDAVP include headache, tachycardia and flushing, and in rare cases hyponatremia and volume overload (due to the antidiuretic hormone effect). For cases of severe bleeding patients can be treated with a VWF/factor VIII that contains clotting concentrate (replacement), such as Humate-P® and Alphanate®. More recently, in December 2015 the FDA approved the use of the first recombinant von Willebrand factor (Vonvendi®) after a phase 3 trial showed good or excellent responses in controlling bleeding for the majority of participants with severe VWD.

B. Physical examination tips to guide management.

The most important guides to whether a patient is responding to treatment are subjective and objective assessment of the patient. The patient can report that he/she is bleeding less or is feeling better, that pain is decreasing, and that range of motion is improving (in the case of hemarthrosis). Assessment of the site of bleeding (e.g., subcutaneous bleeding, incisional bleeding) is important.

C. Laboratory tests to monitor response to and adjustments in management.

A factor VIII level is a good estimation of the effect of treatment on secondary hemostasis. The effect on primary hemostasis (platelets) is difficult to measure. Hemoglobin and hematocrit are surrogate markers for hemostasis.

D. Long-term management.

The long-term management of people with VWD depends on the severity and subtype of their disease. Mildly affected patients can be managed symptomatically. For example, women with type 1 VWD and complaints of menorrhagia may be started on hormonal treatments (e.g., birth control pills) to decrease their menstrual flow.

E. Common pitfalls and side effects of management

Desmopressin should not be given to people with type 2B VWD. Since this subtype of VWD is characterized by increased binding of VWF to platelets, releasing VWF into the circulation by giving desmopressin can result in worsening thrombocytopenia.

VWF concentrates contain both FVIII and VWF and can be dosed based on either of the units. Generally, the first dose given is based on FVIII units and subsequent doses on the VWF:RCoF units.

IV. Management with Co-Morbidities

N/A

A. Renal insufficiency.

Desmopressin in contraindicated if the creatinine clearance is less than 50 milliliters/minute.

B. Liver insufficiency.

Several people who received clotting factor concentrates in the 1980s contracted hepatitis C, and people with VWD may have liver insufficiency because of that or from other causes. If the liver insufficiency results in an additional coagulopathy (because decreased vitamin K-dependent clotting factors are being produced by the liver or because of disseminated intravascular coagulopathy or thrombocytopenia), bleeding in a VWD patient can be difficult to control.

C. Systolic and diastolic heart failure

Desmopressin should be used cautiously in congestive heart failure since it can induce volume overload due to the antidiuretic hormone effect.

D. Coronary artery disease or peripheral vascular disease

Theoretically, giving clotting factor concentrates can make a VWD patient hypercoagulable, so it is important not to give too much clotting factor, especially in the elderly. The guidance of an experienced hematologist is advised.

E. Diabetes or other endocrine issues

Desomopressin should be used cautiously in patients with electrolyte imbalances. It can cause dilutional hyponatremia, especially in the very young and elderly.

F. Malignancy

If thrombocytopenia develops because of malignancy or secondary to the treatment of the malignancy (e.g., chemotherapy), the VWD patient is at even higher risk for bleeding and should be monitored carefully. Some treatments (tyrosine kinase inhibitors) for chronic myelogenous leukemia have been associated with reduced platelet function and can also contribute to increased bleeding in patients who have both conditions.

G. Immunosuppression (HIV, chronic steroids, etc).

No change in standard management

H. Primary lung disease (COPD, asthma, ILD)

No change in standard management

I. Gastrointestinal or nutrition issues

Poor nutrition can lead to vitamin K deficiency, resulting in decreased production of some clotting factors (II, VII, IX, X), which can further contribute to bleeding.

J. Hematologic or coagulation issues

Because all treatment for VWD has a potential thrombotic risk, treatment should be used judiciously.

K. Dementia or psychiatric illness/treatment

No change in standard management.

A. Sign-out considerations while hospitalized.

A patient who is in the hospital with VWD should be followed by a hemophilia team or a hematologist, if available. Any reported increased bleeding must be taken seriously and should be brought to the attention of consulting team or hematologist.

B. Anticipated length of stay.

The length of stay various tremendously and depends on the type of bleed or procedure and the response to treatment. After routine surgical procedures (e.g., tonsillectomy, cholecystectomy, knee replacement), a longer than usual hospitalization can be expected to ensure close monitoring and sufficient hemostasis.

C. When is the patient ready for discharge?

The patient is ready for discharge when sufficient hemostasis is assured--that is, when the initial bleeding episode is controlled and symptoms are decreasing, sufficient time has passed since a procedure/surgery, and there are no signs of excessive bleeding.

D. Arranging for clinic follow-up

If the patient is routinely followed at a designated center for bleeding disorders (often referred to as a hemophilia treatment center, or HTC) or by a hematologist, the center or hematologist should be informed of the patient's admission. The patient is likely to know which center/hematologist is following his or her case and will have a phone contact. If the patient does not have a center or hematologist for routine care, it is important to refer the patient to one upon discharge from the hospital. The following website is a good source for finding a HTC in your area: http://www.cdc.gov/ncbddd/hemophilia/HTC.html

1. When should clinic follow up be arranged and with whom?

Since the bleeding center or hematologist is aware of the admission (and, ideally, follows along during the patient's hospitalization), follow-up can be arranged through them.

2. What tests should be conducted prior to discharge to enable best clinic first visit?

Consulting with the center/hematologist about testing needed prior to discharge is advised.

3. What tests should be ordered as an outpatient prior to or on the day of the clinic visit?

Consulting with the center/hematologist about testing needed prior to discharge is advised.

E. Placement considerations.

Most patients will be able to go home, although some may require home health care, physical therapy, and/or occupational therapy.

F. Prognosis and patient counseling.

The prognosis for most patients with VWD is very good, provided their bleeding is treated or prevented appropriately and that their bleeding issues have improved with the advent of comprehensive care in a designated center that focuses on bleeding disorders.

A. Core indicator standards and documentation.

N/A

B. Appropriate prophylaxis and other measures to prevent readmission.

Most people with VWD are followed routinely at a hemophilia or bleeding disorder treatment center, where they have a comprehensive visit about once a year. The center usually prescribes treatment for use in case of bleeding, which is administered by the patient or a family member at home. Patients with repeated heavy bleeding are usually started on prophylactic treatment with desmopressin or clotting factor to prevent bleeding.

People with VWD are encouraged to follow normal activities and sports, with the exception of high-impact sports (e.g., football, boxing, rugby, wrestling) because of the risk for head injury. Helmets and protective gear are recommended for some sports (skateboarding, skiing, baseball, etc.). Patients on prophylaxis are encouraged to take their prophylactic dose prior to engaging in sports activities.